The overall objective of PARC is to identify the genetic components of the wide inter-individual variation in effectiveness of statin treatment for reducing the risk of coronary artery disease (CAD). Our specific aims will be carried out by an experienced multidisciplinary team of investigators, who have established a strong record of productive interactions. In Aim 1 we will perform a greatly expanded meta-analysis of summary genome-wide association studies (GWAS) in large clinical trials and population cohorts to determine the single nucleotide polymorphisms (SNPs) associated with statin-induced reductions of LDL, the main statin target (~20,000 individuals) as well as the inflammatory marker CRP (~8,000 individuals). In Aim 2, we will identify statin-responsive genes in lymphocyte cell lines derived from PARC participants that mirror in vivo statin responses in these individuals. We will apply multiple genomic approaches, including expression microarrays, transcriptome sequencing, and expression quantitative trait locus analysis, coupled with construction of coexpression networks, to identify statin-responsive genes. This information will be integrated with the GWAS data from Aim 1 and used in Aim 3 to identify the genes and SNPs most strongly related to statin response. In Aim 4, the functional properties of ~20 SNPs and/or genes implicated in mediating statin response in Aim 3 will be validated in appropriate cell models. The top SNPs identified by these approaches, together with others reported to be significantly associated with CAD risk (284 plus 100 ancestry informative markers) will be tested in Aim 5 for their ability to predict CAD outcomes in 3,500 patients from three racial groups who experienced a CAD event while being treated with the most commonly used statins in clinical practice settings, and 3,500 control subjects without Ml, matched for duration of statin exposure. The 48 most significant SNPs will then be tested for associations with lipid and clinical outcomes using data from 18,000 statin-treated patients (6,000 with a cardiovascular event and 12, 000 controls) in an international group of collaborating studies. Another collaborative activity will be replication of genome-wide and candidate SNP associations with statin-induced myopathy, the key adverse event resulting from statin use. Finally this proposal includes a component of the Pharmacogenetics Research Network's NextGen Resequencing Resource that will offer exome resequencing as a means of identifying the full spectrum of genetic variants associated with extremes of drug response and with adverse events. This resource will be used in PARC to identify rare coding SNPs in 20 well-defined cases of statin-associated muscle toxicity. PUBLIC HEALTH RELEVANCE: Statins are the first-line drug treatment for reducing LDL levels and with this, the risk for CAD. However there is considerable variation in response to statin therapy, and many CAD events occur in treated patients. In addition, the potential for statin-induced muscle damage remains a significant concern. The use of advanced genomic analysis of statin-responsive metabolic and inflammatory networks to determine the genetic basis for variation in statin effectiveness will lead to improvements in therapies for reducing risk of CAD.